1. Pulmonary Hypertension: a Deeper Look into WHO Group 1 and 4 Lana Melendres-Groves PH Program Director Pulmonary/Critical Care 1/27/16

2. Objectives Define pulmonary hypertension (PH), pulmonary arterial hypertension (PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) Discuss the classification system of PH Describe the pathophysiology of PAH and CTEPH Detection and diagnosis of PH, PAH and CTEPH A little on management and medications for WHO grp 1 and 4

3. Suspicion of Pulmonary Hypertension Edema Shortness of breath Fatigue Dizziness/syncope Echo findings: – Elevated PASP – Right heart dilation – Right heart dysfunction My attending told me so Presence of other disease processes PFT findings CT chest findings Presence of pulmonary embolism

4. Definition of Pulmonary Hypertension (PH) PH refers to the presence of abnormally high pulmonary vascular pressure Normal mPAP: 8-20mmHg at rest PH: mPAP> 25mmHg at rest

5. How is Pulmonary Arterial Hypertension (PAH) Defined? PAH is a syndrome resulting from restricted blood flow in the pulmonary arterial circulation resulting in increased pulmonary vascular resistance which causes right ventricular strain and ultimately failure Hemodynamic- mPAP >25mmHg definition of PAH:- PCWP <15mmHg - PVR > 3 woods units

6. Clinical Classification of Pulmonary Hypertension (Nice, 2013) 1.1 Idiopathic PAH (IPAH) 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 Associated PAH 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1’. Pulmonary veno-occlusive disease (PVOD) and /or pulmonary capillary hemangiomatosis (PGH) 1”. Persistent pulmonary hypertension of the newborn (PPHN) 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 5.1 Hematologic disorders 5.2 Systemic disorders 5.3 Metabolic disorders 5.4 Others 1. Pulmonary arterial hypertension (PAH) 2. PH due to left heart disease 3. PH due to lung disease and/or hypoxia 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. PH with unclear multifactorial mechanisms

7. Why do I care so much? And Why should you care so much?

8. PH is a Rapidly Progressive, Ultimately Fatal Condition WHO Group 1 PAH WHO Group 2 Left-heart related WHO Group 3 Lung/hypoxia related WHO Group 4 CTEPH Based on a sample of 194 patients followed between 1981 and 1986, median survival was estimated at 2.8 years (IPAH) In a study of 379 patients referred to a single center between 1992 and 1998, patients with Group 2 PH had 7x higher mortality than left- sided heart failure alone 5-year survival rate in study of 84 total COPD patients was 36% in those with PH vs 62% in patients without PH In a study of 79 IPF patients, the 6.5- year mortality rate was 60% among those with PH vs 30% in patients with IPF alone Mean survival 6.8 years without surgical treatment in a study of 48 Japanese patients

9. Pathogenesis of PAH: Aberrant Pathways

10. Loss of Biological “Balance” in PAH Vasodilation Apoptosis Vasoconstriction Proliferation Vasodilation Apoptosis Vasoconstriction Proliferation

11. SMC Endothelium elastic elasticlamina injury serum leak SMC PROLIFERATION & MIGRATION Pathobiology of PAH

12. Prevalence of PAH Based of the French National Registry from ‘02-’03 for PAH and IPAH: – Consecutive adult patients 17 French specialty centers – Prevalence of PAH: 15 cases/million – Prevalence of IPAH: 5.9 cases/million

13. Distribution of PAH Subtypes French Registry (n=674) IPAH 39.2% FPAH 3.9% CTD 15.3% CHD 11.3% Portal htn 10.4% Drugs and toxins 9.5% HIV 6.2% REVEAL (n=2525) IPAH 46.2% APAH 50.7% – CTD/CVD 49.9% – CHD 19.5% – Drugs and toxins 10.5% – Portal htn 10.6% – Other 5.5% – HIV 4.0% FPAH 2.7% Other 0.4%

14. Prevalence of PAH in Connective Tissue Diseases Systemic lupus erythematosis (SLE): 0.5% to 17% Mixed Connective tissue disease (MCTD): up to 25% Systemic Sclerosis: 8% to 27% SLE MCTD Systemic Sclerosis

15. Drugs and Toxins Associated with PAH Definite -Aminorex -Fenfluramine -Dexfenfluramine -Toxic rapeseed oil -Benfluorex -SSRIs Likely -Amphetamines -L-tryptophan -Methamphetamines -Dasatinib Possible -Cocaine -Phenylpropanolamine -St. John’s Wort -Chemotherapeutic agents -Interferon alpha and beta -Amphetamine-like drugs Unlikely -Oral contraceptives -Estrogen -Cigarette smoking

16. Portal Hypertension Prevalence of PAH in portal htn ranges from 2% to 6% Risk of developing PAH increases with duration of portal hypertension Liver disease is most common cause of portal hypertension, but it can be secondary to nonhepatic causes

17. Switching WHO Groups On to Group 4: CTEPH

18. What is CTEPH? Vascular disorder characterized by: – Organized thrombotic obstruction in the pulmonary arteries – May involve small-vessel vasculopathy that is indistinguishable from idiopathic PAH Defined by the following observations after 3 months of effective anticoagulation: - mPAP >25mmHg - PCWP <15mmHg - Mismatched perfusion defects

19. Epidemiology of CTEPH Each year, approximately 600,000 individuals in the US have an acute PE Estimated incidence of CTEPH after acute PE is 0.5%-4% CTEPH registry showed that 75% of pts with CTEPH had prior acute PE

20. Pathogenesis of CTEPH The result of persistent macrovascular obstruction and a vasoconstrictor response that lead to a secondary small-vessel arteriopathy The arteriopathy results in PH, and reductions in the pulmonary-artery diameter due to thrombosis and vasoconstriction results in adverse vascular remodeling

21. Mechanisms of Small Vessel Disease in CTEPH 1.Vascular pathology- mainly obstruction of “small” subsegmental elastic pulmonary arteries Features - Small artery occlusion with stenoses, webs, and bands - Similarity/overlap with idiopathic PAH 2. Vascular pathology- classic pulmonary arteriopathy of small vascular arteries and arterioles distal to nonobstructed elastic pulmonary arteries Features - intimal proliferation and/or increased media thickness + plexiform lesions - increased pressure and flow  endothelial dysfunction 3. Vascular pathology- pulm arteriopathy distal to obstructed pulmonary arteries Features - poor perfusion  endothelial dysfunction

22. McGoon et al. Chest 2004;126:14S-34S No further evaluation for PAH Is PAH likely? Echo Is there a reason to suspect PAH Clinical history (symptoms, risk factors, family Hs.), Exam, CXR, ECG Is PAH due to LH disease? Echo Is PAH due to CHD? Echo with contrast Is PAH due to CTD, HIV? Serologies Dx Scleroderma, SLE, other CTD, HIV: Medical treatment of PAH and further evaluation for other contributing causes, including RHC Dx abnormal morphology; shunt: Surgery. Medical treatment of PAH or evaluation for further definition or other contributing causes, including R&LHC if necessary Dx LV systolic, diastolic dysfunction; valvular disease: Appropriate treatment and further evaluation if necessary, including R&LHC TRV to measure RVSP; RVE; RAE; RV Dysfunction: yes Rationale no yes no PAH: Detection and Diagnosis Is chronic PE suspected? VQ scan

23. McGoon et al. Chest 2004;126:14S-34S Dx parenchymal lung disease, hypoxemia, or sleep disorder: Medical treatment, oxygen, positive pressure breathing as appropriate, and further evaluation for other contributing causes, including RHC if necessary yes Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/ response to treatment with serial reassessments Document PA and RA pressures, PCWP (LV or LA pressure if PCWP unobtainable or uncertain), transpulmonary gradient CO, PVR, SvO 2, response to vasodilators: Confirm PAH, or IPAH if no other cause identified Discuss genetic testing and counseling of IPAH What limitations are caused by the PAH? Functional class; 6-minute walk test What are the precise pulmonary hemodynamics? RHC Is chronic PE suspected? VQ scan Is PAH due to lung disease or hypoxemia? PFTs, arterial saturation Is chronic PE confirmed and operable? Pulmonary angiogram Anatomic definition (CT, MRI may provide additional useful but not definitive information): Thromboendarterectomy if appropriate or medical treatment; clotting evaluation; a/c yes no VQ normal PAH: Detection and Diagnosis

24. Right Heart Catheterization: Diagnostic Gold Standard Hemodynamics: – RAP, mPAP, PCWP, CO/CI, PVR Saturations: – Rule out shunts Angiography: – Vessel properties – CTEPH Vasodilator response

25. PAH/CTEPH General Care Fluid/volume control Oxygen Anticoagulation Diuretics Low sodium diet Daily wgts/I&Os Hypoxia is a potent vasoconstrictor and can elevate PA pressure IPAH/CTEPH patients on anticoagulation Consideration in other WHO group 1 patients

26. Surgical Treatment of CTEPH Pulmonary thromboendarterectomy (PTE) is the treatment of choice for patients with CTEPH CTEPH patients should be on life-long anticoagulation with INR between 2.0 and 3.0 Surgery should not be delayed in favor of medical therapy

27. CTEPH Operability Assessment Candidacy for PTE should be determined by an expert center – Interdisciplinary team: cardiologist/pulmonologist, radiologist, and expert surgeon Both pulmonary angiography and CT scanning are useful diagnostic tools for CTEPH operability

28. Surgical Treatment of CTEPH Pulmonary thromboendarterectomy (PTE) – Only potentially curative treatment – Removes obstructive, hardened thromboembolic material – Improvements in 6MWD, pulmonary function, and tricuspid regurgitation

29. Nonsurgical Candidates or Persistent PH Despite Surgery A systemic review indicated that 11% to 25% of post-PTE patients had residual PH. A 2011 registry of 679 CTEPH patients showed a 37% rate of being deemed inoperable What do you do with them? – Medical management

31. Therapeutic Pathways

32. Therapies The only groups that have been approved for the specialized medications for pulmonary hypertension are WHO Group 1 (PAH) and Group 4 (CTEPH) The other groups require treatment of the underlying condition causing the elevated pressures.

33. Therapeutic Options for PAH FDA approved PAH therapies Prostanoids – Epoprostenol (flolan/veletri) – Treprostinil (IV/SQ/Inhaled) – Inhaled Iloprost (Ventavis) – Oral treprostinil (Orenitram) – Selexipag (Uptravi) ERA’s – Bosentan (Trecleer) – Ambrisentan (Letairs) – Macitentan (Opsumit) PDE-5 Inhibitors – Sildenafil (Revatio) – Tadalafil (Adcirca) Soluable Guanylate Cyclase Stimulator – Riociguat (Adempas) (Only medication currently approved for the use in CTEPH)

34. Prostanoids Prostacyclin (PGI2)- member of the eicosanoids family, inhibits platelet activation and effective vasodilator. Prostacyclin released by healthy endothelial cells. Deficiency in PAH patients Several routes of administration: – IV/parenteral, SQ, Inhaled, oral

35. IV Prostanoids Epoprostenol- Flolan and Veletri – Half-life approximately 2-5min Treprostinil- Remodulin – Half-life several hours – Both administered in ng/kg/min – Dosing never changes even if weight does, start weight remains the same throughout duration of therapy.

36. Single Lumen Hickman Catheter Never stop infusion Never draw labs from line Never flush

37. CADD Legacy Pump

38. Oral Prostacyclin Treprostinil (Orinetram) – Antiplatelet and vasodilatory actions, including pulmonary vasodilation Selexipag (Uptravi) – Most recently approved in Dec 2015 – Not a substitute for parenteral therapy

39. Endothelin Receptor Antagonist Endothelian-1 (ET-1) levels are increased in PAH and found in the precapillary pulmonary microvasculature which is the site of the increased vascular resistance in PAH. Bosentan- 62.5 to 125mg BID – Monitor for liver toxicity Ambrisentan- 5-10mg daily Macitentan- 10mg daily

40. Phosphodiestrase-5 Inhibitors PDE5 Inhibitor- blocks the degradative action of phosphodiesterdase type 5 on cyclic GMP in smooth muscle cells resulting in vasodilation of the vessels. Sildenafil- 20-80mg TID Tadalafil- 20-40mg daily

41. Guanylate Cyclase Stimulator Riociguat has a dual mode of action – Synergist with endogenous nitric oxide – Directly stimulating guanylate cyclase independent of NO availability FDA approved for both use in PAH as well as inoperable or residual CTEPH

42. Cost per Year Ambrisentan (Letairis)- $76,047.60 Bosentan (Tracleer)- $76,543.20 Tadalafil (Adcirca)- $18,316.80 Epoprostenol (Flolan)- $34,170 Oral Treprostinil (Orinetram)- $500,000 Triple therapy can be over $130, 000/yr just for specialty medications.

43. Ongoing Management Standard of care is for PAH patients to be established with a PH center for ongoing care. – Multidisciplinary approach to care Patients on advance therapies to be seen every 3 months if not more frequently Ongoing escalation of care, more evidence coming out showing the importance of combination therapies up-front.

44. Questions